This application is being submitted to PA-18-591 in accordance with NOT-OD-18-194. Down Syndrome (DS) is the most common genetic cause of intellectual disability. It is associated with impaired language, cognition, and adaptive functioning, three areas of difficulty that are shared by children with other neurodevelopmental disorders for whom empirically-supported interventions exist, such as autism spectrum disorder (ASD). Despite this, current knowledge on evidence-based early interventions to address these challenges in young children with DS is limited. Moreover, many clinical trials for common comorbidities in DS, such as ASD, explicitly exclude participants with DS and other neurogenetic disorders. Given that ~20% of children with DS meet criteria for ASD and most individuals with DS present with social cognitive weaknesses, social functioning may be an important intervention target. However, additional research is needed to characterize social functioning in young children with DS, so to inform intervention needs and factors associated with response to treatments targeting social (and closely related language) skills in DS. The current study proposes a supplement to an Autism Centers of Excellence (ACE) network that will examine response to intensive, comprehensive early intervention in a sample of children with DS with varying degrees of ASD symptomatology. As part of the study, novel experimental measures of social functioning, as well as standardized measures of ASD symptoms, language, and cognition, are assessed before and after intervention to learn about response to treatment in DS as well as predictors and mechanisms of this response. The treatment used in this study is the Early Start Denver Model (ESDM), a comprehensive evidence-based intervention developed for young children with ASD which targets social, language, and adaptive functioning. A sample of 40 children with DS, aged 12-48 months, will be recruited and randomized to receive 20 hours/week of ESDM for 6 months, or to treatment as usual, stratified by age and ASD symptom severity. An age-matched subsample of children from the parent study will be included to compare the magnitude of treatment response in DS vs. children with ASD. Pre- and post-treatment evaluations mirror the parent study, and include comprehensive evaluation using standardized measures of cognitive, language, social, adaptive functioning, and ASD symptoms, and eye tracking paradigms measuring social learning domains and ratings of the social engagement between parents and children during play. Consistent with the purpose, scope and methodology of a pilot RCT, the proposed supplement, while likely underpowered to detect statistically significant findings, will inform the development of a full-scale clinical trial designed to test improvement in language, cognitive, and adaptive outcomes in children with DS. This is in line with the INCLUDE project?s goal of stimulating additional efforts that will lead to progress about DS and possibly impactful treatments. This supplement will address two specific aims. First, we will examine whether children with DS show greater gains from ESDM compared to TAU. We also will explore whether the gains in the DS group randomized to ESDM are comparable to those observed in a subset of children with ASD treated with ESDM in the parent study and whether comorbid ASD symptoms in the DS group are associated with the response to ESDM. Second, by examining profiles of social functioning in the sample combining the children recruited in the supplement (DS) and the parent study (ASD), we will evaluate whether patterns of social cognition and social motivation abilities predict treatment response using novel eye-tracking tasks developed for the parent grant, as well as standardized tests of ASD symptomatology and social functioning. This will allow us to examine how social processing differences between and within diagnostic groups affect treatment response. This proposal addresses the INCLUDE Project objective of inclusive clinical research for individuals with DS. Given the very limited research on comprehensive, intensive early intervention in DS, it is crucial to assess whether interventions developed for other neurodevelopmental disorders yield positive results in DS. The parent study focuses on children with ASD, which is a common comorbidity in DS. This proposed supplement meets the NIMH priorities of examining a mental health condition comorbid with DS, namely ASD. The study design also takes a dimensional approach to social functioning (consistent with NIMH priorities), with the understanding that children with DS likely show distinct patterns of strengths and weaknesses within aspects of social functioning. A better understanding of how different profiles of strengths and weaknesses across and within disorders predict response to intervention is critical to the development, optimization and customization of existing interventions across different neurodevelopmental disorders. This supplement also enhances the parent grant by expanding the investigation of predictors of response to ESDM treatment to a transdiagnostic sample of children with neurodevelopmental disorders, who will display different patterns of strengths and weaknesses across domains of social functioning. By examining treatment outcomes from ESDM in well-characterized samples of children with DS and ASD, we will provide critical insight on how ESDM interacts with the different social profiles that characterize ASD and DS. This will be informative for developing and adapting treatment targets and strategies across diagnostic boundaries, thus promoting improved outcomes, mitigating lifespan disability, reducing societal costs and improving personal well-being and productivity of individuals with neurodevelopmental disorders.